Crystallization of iodixanol using milling

ABSTRACT

This invention relates to the manufacture of iodixanol(1,3-bis(acetamido)-N,N′-bis[3,5-bis(2,3-dihydroxypropylaminocarbonyl)-2,4,6-triiodophenyl]-2-hydroxypropane), more specifically to the purification of iodixanol by crystallization by using wet milling.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims benefit of priority under 35 U.S.C.§119(e) to U.S. Provisional Application No. 61/227,106 filed Jul. 21,2009, the entire disclosure of which is hereby incorporated byreference.

TECHNICAL FIELD

This invention relates to the manufacture ofiodixanol(1,3-bis(acetamido)-N,N′-bis[3,5-bis(2,3-dihydroxypropylaminocarbonyl)-2,4,6-triiodophenyl]-2-hydroxypropane),more specifically to the purification of iodixanol by crystallization.

BACKGROUND OF THE INVENTION

Iodixanol is the non-proprietory name of the chemical drug substance ofa non-ionic X-ray contrast agent marketed under the trade nameVisipaque™. Visipaque™ is one of the most used agents in diagnosticX-ray procedures and is manufactured in large quantities.

The manufacture of such non-ionic X-ray contrast agents involves theproduction of the chemical drug substance (referred to as primaryproduction) followed by formulation into the drug product (referred toas secondary production). Primary production of iodixanol involves amulti step chemical synthesis and a thorough purification process. For acommercial drug product it is important for the primary production to beefficient and economical and to provide a drug substance fulfilling thespecifications, e.g. as expressed in the US Pharmacopeia.

A number of methods are known for the preparation of iodixanol. Theseare all multi step chemical synthetic processes and the cost of thefinal formulated product thus mainly depends on these processes. It istherefore important to optimize the processes both for economic andenvironmental reasons.

Three main chemical synthetic processes are known for the preparation ofiodixanol, all of which start with 5-nitroisophthalic acid. In the firstprocess described in EP 108638, which document is hereby incorporated byreference, the final intermediate5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide(hereinafter “Compound A”) is reacted with a dimerisation agent such asepichlorohydrin to yield the drug substance, see Scheme I.

The overall yield in this process is relatively low and the purificationof the end product iodixanol is expensive and time consuming. Thepurification process described in EP patent 108638 involves purificationby preparative liquid chromatography. The use of preparative liquidchromatography is a serious disadvantage in industrial processes inparticular due to the high costs involved.

Several attempts have been made to find alternative manufacturingprocesses. Attempts to increase the yield of the chemical synthesis ispublished by Priebe et. al. (Acta Radiol. 36 (1995), Suppl. 399, 21-31).This publication describes another route which avoids the difficult laststep of the process of Scheme I. However, the route involves eightreaction steps from 5-nitroisophthalic acid, which is undesirable, andone of the steps includes chlorination with thionyl chloride, which isextremely corrosive. Also, the introduction of the iodine atoms takesplace very early in the sequence, which is disadvantageous as iodine isthe most expensive reagent in the process. The yield and finalpurification method for this route have not been reported.

The third route to iodixanol involves the synthesis of5-amino-2,4,6-triiodoisophthalic acid (WO 96/37458) and then itsdichloride (WO 96/37459), followed by conversion into Compound A (U.S.Pat. No. 5,705,692) and finally dimerisation as in the process of SchemeI. This method thus has the same disadvantages as the first process, andalso uses an undesirable acid chlorination step.

A common system for purification of the crude product in the final stepof the primary production process, avoiding the liquid chromatographymethod, has been purification by crystallization. To achieve the desiredpurity, the crude iodixanol produced by the synthetic chemical processis crystallized twice. The process is time consuming and takes about 3days for the first crystallization and about 2 days for the second one.Hence, the crystallization process is very demanding in terms of timeand equipment size, it will take several days to perform and is often abottleneck in industrial scale processes.

WO 99/18054 describes a process for the crystallization of i.a.iodixanol where the crystallization is effected with high thermalenergy, specifically under elevated pressure and at a temperature abovethe boiling point of the solution at atmospheric pressure.

WO 00/47549 describes a process for the preparation of iodixanol whereunreacted Compound A is precipitated from the reaction mixture andrecovered for reuse in a later batch.

It is hence a desire to shorten the crystallization time and alsoimprove the crystallization step in order to increase the purity of thefinal product.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows agglomerates of iodixanol produced in a crystallizationstep according to prior art. Scale: 1 unit=120 μm.

FIG. 2 shows iodixanol particles produced in a crystallization stepaccording to the present invention. Scale: 1 unit=30 μm.

FIGS. 3A and 3B show iodixanol particles produced in a crystallizationstep according to the present invention. Scale: 1 unit=30 μm.

SUMMARY OF THE INVENTION

The present invention provides improvements to the crystallization ofiodixanol.

Thus viewed from one aspect the invention provides a process for thepurification of a crude product comprising iodixanol by crystallization,wherein the crystallization involves wet milling.

The process according to the present invention reduces the process timefor the crystallization steps and improves the washing and hence thepurity of the final product.

DETAILED DESCRIPTION OF THE INVENTION

The processing time for the first crystallization is substantiallylonger than for the second one because of the higher concentration ofimpurities at this stage of the process. Due to the slow kinetics, bothcrystallizations are run at high initial supersaturation and during thecrystallization process it is formed large agglomerates, often of morethan 100 μm in diameter. These agglomerates are shown in FIG. 1.Agglomeration significantly reduces the available total surface area forcrystal growth and therefore prolongs the process time to achieve thedesired yield.

It has now surprisingly been found that it is possible to performdeagglomeration during the crystallization process by using wet milling.

Thus viewed from one aspect, the invention provides a process for thepurification of a crude product comprising iodixanol by crystallization,wherein the crystallization solution is deagglomerated by wet milling.

The use of wet milling will significantly reduce the agglomeration ofiodixanol crystals and by this reduce the process time for thecrystallization steps. In cases where two crystallization steps areperformed, the use of wet milling will be able to reduce the processtime from about three days to less than two days for the firstcrystallization and from about two days to less than 1 day for thesecond crystallization.

Further, the use of wet milling in the crystallization step will alsoimprove the purity of the final product. The purification process isfinalized by filtering the precipitated iodixanol, preferably asunagglomerated crystals, from the solvents and finally washing thecrystals with an alcohol such as methanol. The agglomerates of iodixanolcrystals will also entrap mother liquor that needs to be removed bywashing. By significantly reducing the agglomeration and hence theinclusion of mother liquor, a more effective washing of the crystals isachieved and also improved purity of the final product.

FIG. 1 shows agglomerates produced during a crystallization processaccording to prior art. It can be seen that the agglomerates have a meansize in the area of about 120 μm. FIG. 2 on the other hand showsparticles produced under a process according to the present invention,and it can be seen that the particles are single crystals or very smallagglomerates. The size of these particles is less then about 30 μm.

According to the present invention wet milling can be performed usingany kind of mill, e.g. disc mills, colloid mills and other shear mixers.

Depending on the type of mill used, the mill can be mounted either intothe crystallizer or in-line to the crystallizer. When mounted in-line tothe crystallizer the crystallization solution is circulated between thecrystallizer and the mill.

The mill can be used continuously throughout the crystallization, butnormally a certain period at the start of the crystallization issufficient to achieve the desired results.

The crude product referred to in the present invention can be obtainedfrom the processes known from the state of the art, e.g. from thedimerisation process illustrated in Scheme I above. The dimerisationstep itself may be carried out as described in European patent 108638and WO 98/23296, for example using epichlorohydrin,1,3-dichloro-2-hydroxypropane or 1,3-dibromo-2-hydroxypropane as thedimerisation agent, with epichlorohydrin being most preferred. Thereaction is usually carried out in a solvent such as 2-methoxyethanol,methanol, 1-methoxy-2-propanol or a mixture of 2-methoxyethanol or1-methoxy-2-propanol and water, and generally results in the conversionof 40 to 60% of Compound A to iodixanol.

Hence, in a second aspect of the invention it is provided a process forthe manufacture of iodixanol comprising the steps of:

-   -   a) reacting        5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide        with a dimerisation agent in the presence of a solvent    -   b) purifying the reaction product from step a) in a        crystallization procedure    -   c) deagglomerating the crystallization solution in the        crystallization procedure by wet milling    -   d) filtering and washing the product from step c)

The crude product from the dimerisation and following work-up steps ispreferably in aqueous solution with small traces of organic solvent. Thecrude product normally contains about 75-90 weight % iodixanol, 3-10weight % iohexyl, 0-7 weight % Compound A, and also minor amounts ofother impurities. The most important impurities in the reaction withregard to work-up consequences are the so-called backpeaks. This termrefers to retention times in reversed phase HPLC, where the backpeakshave slightly longer retention times than iodixanol itself. Most of thebackpeaks are either trimers or O-alkylated dimers. This crude productis preferably the starting material for the further purification bycrystallization according to the present invention.

The invention is illustrated further by the following examples that arenot to be construed as limiting the invention in scope to the specificprocedures or products described in them.

Example 1 shows a conventional crystallization process according toprior art without the use of wet milling. FIG. 1 shows agglomerates ofiodixanol produced (1 unit=120 μm). The process reaches a yield of 80%after 54 hours. From the comparative example 2 showing the same processwith the use of wet milling, it can be seen that a yield of 80% isreached as early as after 32 hours. In addition it can be seen that thepurity of the final product is increased. FIG. 2 shows iodixanolparticles produced (1 unit=30 μm).

In example 3 an optimized process with wet milling is described. Becauseof the shorter crystallization times involved, solvent can be added atan earlier stage than in a process according to prior art. In thisprocess it can be seen that a yield of more than 80% is reached afteronly 23 hours.

Example 4 describes the process according to the present invention in alarger scale and with the use of a colloid mill. The crude productcontained about 60% more backpeaks than in a comparable prior artprocess. However, by reducing the agglomeration by milling, the backpeakcontent after the first crystallization was similar to the backpeakcontent after the first crystallization in the prior art process. As forthe prior art process, the product specification was met first after afurther recrystallization not described in the example.

EXAMPLES Example 1

305 g of crude product containing 253 g iodixanol, 17.8 g Compound A,22.5 g iohexyl and 5.1 g backpeaks was dissolved in a mixture of waterand 1-methoxy-2-propanol (PM) in a 1 liter vessel equipped with the astirrer (with a magnet driven shaft), condenser and heating jacket. Theamount of water and PM in the solution was 105 g and 442 g respectively.The solution was heated to reflux at atmospheric pressure and seededwith 2.4 g seed particles of iodixanol. Further addition of PM was doneas follows:

Start addition of PM (hrs Amount Addition after seeding) of PM (g) time(hrs) 12 111 13 25 276 8

The yield of iodixanol was as follows:

Time (hrs Yield of after seeding) iodixanol (%) 12 2 24 18 32 50 48 7954 80

The product at the end of the crystallization was filtered and washedwith methanol. The purity of the product is given below (HPLC):

Substance (%) Iodixanol 98.56 Compound A 0.10 Iohexol 0.21 Backpeaks1.07

FIG. 1 shows iodixanol agglomerates produced.

Example 2

305 g of crude product containing 253 g iodixanol, 17.8 g Compound A,22.5 g iohexyl and 5.1 g backpeaks was dissolved in a mixture of waterand 1-methoxy-2-propanol (PM) in a 1 liter vessel equipped with the astirrer (with a magnet driven shaft), disc mill, condenser and heatingjacket. The amount of water and PM in the solution was 105 g and 442 grespectively. The solution was heated to reflux at atmospheric pressureand seeded with 2.4 g seed particles of iodixanol. Further addition ofPM was done as follows:

Start addition of PM (hrs Amount Addition after seeding) of PM (g) time(hrs) 12 111 13 25 276 8

The yield of iodixanol was as follows:

Time (hrs Yield of after seeding) iodixanol (%) 12 57 24 71 32 80 48 8354 83

The product at the end of the crystallization was filtered and washedwith methanol. The purity of the product is given below (HPLC):

Substance (%) Iodixanol 99.00 Compound A 0.05 Iohexol 0.05 Backpeaks0.86

FIG. 2 shows iodixanol particles produced.

Example 3

305 g of crude product containing 253 g iodixanol, 17.8 g Compound A,22.5 g iohexyl and 5.1 g backpeaks was dissolved in a mixture of waterand 1-methoxy-2-propanol (PM) in a 1 liter vessel equipped with the astirrer (with a magnet driven shaft), disc mill, condenser and heatingjacket. The amount of water and PM in the solution was 105 g and 442 grespectively. The solution was heated to reflux at atmospheric pressureand seeded with 2.4 g seed particles of iodixanol. Further addition ofPM was done as follows:

Start addition of PM (hrs Amount Addition after seeding) of PM (g) time(hrs) 10 111 4 14 276 4

The yield of iodixanol was as follows:

Time (hrs Yield of after seeding) iodixanol (%) 10 51 14 65 18 78 23 8135 82

The product at the end of the crystallization was filtered and washedwith methanol. The purity of the product is given below (HPLC):

Substance (%) Iodixanol 99.0 Compound A 0.05 Iohexol 0.05 Backpeaks 0.86

Example 4

An aqueous solution of crude iodixanol product was concentrated in avessel and 1-methoxy-2-propanol (PM) was added. The content of water wasthen adjusted to the desired level. The solution contained about 60 kgiodixanol, 4 kg Compound A, 4 kg iohexyl and 2 kg backpeaks. The vesselwas equipped with a stirrer, condenser, colloid mill (MK2000/4 fromIKA™) in loop to the vessel and heating jacket. The crude productcontained about 60% more backpeaks than in a comparable prior artprocess. The amount of water and PM in the solution was 19 kg and 58 kgrespectively. The solution was heated to reflux at atmospheric pressureand seeded with 0.56 kg seed particles of iodixanol. Further addition ofPM was done as given in the table below. The water content was reducedby 14% by distillation during the crystallization.

Start addition of PM (hrs Amount Addition after seeding) of PM (kg) time(hrs) 10 19 6 16 38 6

The yield of iodixanol was as follows:

Time (hrs Yield of after seeding) Iodixanol (%) 11 61 14 68 37 88

The product at the end of the crystallization was filtered and washedwith methanol. The purity of the product is given below (HPLC):

Substance (%) Iodixanol 98.7 Compound A 0.07 Iohexol 0.04 Backpeaks 1.09

The iodixanol particles produced using the mill during for the first 11hours of a total crystallization time of 37 hours, are shown in FIGS. 3Aand 3B. FIG. 3A shows the particles 13 hours after seeding and the FIG.3B shows the particles 37 hours after seeding.

All patents, journal articles, publications and other documentsdiscussed and/or cited above are hereby incorporated by reference.

1. An improved process for the purification of a crude reaction mixtureresulting from the dimerisation of Compound A comprising iodixanol,Compound A, iohexol and backpeaks comprising the step of wet millingsaid crude reaction mixture during the crystallization process of saidcrude reaction mixture.